Sepsis-inducing toxins have been found associated with pathogenic bacteria, viruses, plants and venom. Among the well-described bacterial toxins are the endotoxins or lipopolysaccharides (LPS) of the gram-negative bacteria. These molecules are glycolipids that are ubiquitous in the outer membrane of all gram-negative bacteria, which are believed responsible for gram-negative sepsis. This type of sepsis is an extremely common condition and is often fatal.
A number of approaches for treating sepsis have been attempted. These include use of antibodies to LPS, use of antibodies to tumour necrosis factor, use of a soluble TNF receptor, use of a soluble interleukin-1 (IL-1) receptor, to name a few. While each approach has some efficacy, the overall results have been disappointing.
Others have attempted to design and study proteins which bind LPS/endotoxin, and illustrative reports of these attempts appear in Rustici, A. et al. Science (1993) 259:361-364; Matsuzaki, K. et al. Biochemistry (1993) 32:11704-11710; Hoess, A. et al. EMBO J (1993) 12:3351-3356; and Elsbach, P. et al. Current Opinion in Immunology (1993) 5:103-107. In fact, upon introduction of LPS into the blood, it may bind to a protein termed lipopolysaccharide-binding protein (LBP). Inhibition of LBP, e.g., with an anti-LBP antibody, has been suggested as therapeutically useful for treating endotoxin-mediated sepsis (International Patent Application No. PCT/US90/04250, filed Jul. 30, 1990). Also, work from several laboratories has shown that plasma lipoproteins, particularly high-density lipoproteins (HDL), bind and neutralise LPS (Skarnes et al., 1968, J. Bacteriology 95:2031; Flegel et al., 1993, Infect. Immunol. 61(12):5140) and that these particles may constitute the LPS-neutralising activity in plasma.
Previous treatments for endotoxin mediated and/or associated diseases has been retrospective (i.e., after development of clinical illness) and has been limited to chemotherapeutic intervention. Prevention measures were not achieved with such treatments.
Thus, there is a need in the art for an effective agent for neutralising gram-negative endotoxin (i.e., LPS), in order to prevent or alleviate symptoms of sepsis and septic shock.
The hydrophobic lactic acid bacteria and bifidobacteria of the present invention provide additional compounds which are capable of binding endotoxins and ameliorating/preventing its effects.